Technical Field
The present invention relates to a composition for treating a neuroinflammatory disease comprising a N-carbamoylated urethane compound. In particular, the present invention relates to a composition for treating a neuroinflammatory disease, the composition comprising a N-carbamoylated urethane compound which has an effect of inhibiting the activity of microglia or astrocytes and the production of nitric oxide (NO) and TNF-α, and suppressing the expression of IL-1β and iNOS genes.
Discussion of the Background
Inflammatory reactions are caused by various inflammatory mediators and immune cells in the local blood vessels and body fluids when there are tissue (cell) damage or infections with foreign agents (such as bacteria, fungi, viruses, and various allergens), while exhibiting a series of complex physiological responses such as the activation of enzymes, the secretion of inflammatory mediators, the infiltration of body fluids, the migration of cells and the destruction of tissues; and external symptoms such as erythema, edema, fever, and pain. Under normal conditions, the inflammatory reactions remove the external infectious agents and regenerate the damaged tissues to recover the normal function of the afflicted organism. However, when the external infectious agents or antigens are not removed or the inflammatory reactions occur excessively or maintain continuously due to internal substances, damages to mucosal layers of tissues may occur and thus lead to diseases such as cancer in some cases.
Recently, it has been found that an inflammatory reaction is one of the main mechanisms causing neurodegeneration. In other words, microglia, which are immune cells present in the central nervous system, can be activated by various exogenous and endogenous substances. Activated microglial cells then produce and release substances including inflammatory cytokines such as TNF-α and IL-1β, nitric oxide, prostaglandins, and superoxides. The production of these substances induces an immune response in the short term, while its excessive or sustained production induces the death of adjacent neurons and eventually leads to neurodegeneration. In addition, since substances released from apoptotic neurons may cause microglial cells to re-activate, neurodegeneration falls into a constant vicious circle. In fact, it has been reported that various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, Creutzfelt-Jakob Disease (CJD) and multiple sclerosis are associated with the activation of microglial cells.
Indeed, activated microglial cells in the brain of patients with Parkinson's disease have been observed (See Hunot et al., 1999; Knott et al., 2000), while the similar observation was detected in animal models of Parkinson's disease by using 1-methyl-4-phenyl-1,2,3,6-tetratetrahydropyridine (MPTP) (See Kohutnicka et al., 1998; Liberatore et al., 1999; Dehmer et al., 2000; Wu et al., 2002). In addition to Parkinson's disease, activated microglial cells have been also observed in various neurological diseases or disorders such as Huntington's disease (See Chen et al., 2000; Tomas et al., 2003; Wang et al., 2003), Alzheimer's disease (Benvensite et al., 2001), Lou Gehrig's disease (See Kriz et al., 2002; Van Den Bosch et al., 2002; Zhu et al., 2002), and localized and ischemic stroke (See Yrjaeikki et al., 1998; Arvin et al., 2001), as well as in traumatic head injuries (See Sanches Meijia et al., 2001).
Microglial cells are ones which perform the primary immune function in the central nervous system. They maintain their shape of thin, long branches and thin cell bodies. Upon the existence of endogenous or exogenous toxins, microglial cells change into their activated shape of thick, short branches and fat cell bodies in order to protect neurons from those toxins. Unlike normal microglial cells, activated microglial cells perform phagocytosis actively, proliferate, and produce inflammatory mediators by inducing the expression of the genes of cytokines (such as TNF-α, IL-1β and IL-6), chemokines, iNOS (inducible nitric oxide synthase), and COX-2 (cyclooxygenase-2). In one aspect, the activation of microglial cells leads to the removal of damaged cells and the protection of neurons from externally invading agents such as bacteria and viruses. In another aspect, however, nitric oxide produced by iNOS and prostaglandins, TNF-α and the like produced by COX-2 are toxic to neurons. As a result, the activation of microglial cells may aggravate the neuronal damage.
In conclusion, since the neuroinflammatory response, which is represented by the activation of microglial cells among various types of nerve cells, plays an important pathological role in various nerve tissue damage, it is suggested that it would be possible to inhibit the neural damages by suppressing the activation of inflammation caused by microglial cells, leading to the development of clinically applicable preventive and therapeutic agents for a neuroinflammatory disease.